1. Field of the invention
The present invention relates to medical metallic materials, especially medical tools for use in circulatory systems, whose surface is modified to improve antithrombogenicity and biocompatibility. More particularly, the present invention relates to the reliable introduction of a biologically active compound onto the surface of a base metal via a linker, thereby bringing about a great improvement in the antithrombogenicity and biocompatibility of the base metal. Also, the present invention is concerned with a method for preparing such a medical metallic material and with the use of the metallic material in the medical field.
2. Description of the Prior Art
For use in substituting for congenitally or postnatally defective valves of the heart, artificial cardiac valves are generally classified into two groups: valves made of tissues and mechanical valves, which are made of metallic materials. Tissue values show excellent biocompatibility, but poor internal durability due to calcification. On the other hand, mechanical valves endure for extended periods in vivo, but have the disadvantage of forcing the patients to take anticoagulants throughout their lifetime because they are likely to generate thrombus. In spite of extensive research, satisfactory advance has not been yet achieved in the antithrombogenicity of mechanical valves. Indeed, not only is it virtually impossible to prevent thrombogenesis, a normal physiological function of the body, but also its mechanism has not been disclosed completely.
Extensively conducted for the treatment of coronary stenosis is percutaneous transluminal coronary angioplasty in which an intraaortic balloon catheter is inserted within the coronary artery to expand the blood vessel. This operation brings about relatively good results, and development has been and continues to be ongoing in the processes and tools for percutaneous transluminal coronary angioplasty. However, such problems as acute closure and restenosis still remain unsolved.
In order to prevent restenosis, stents, which are spring-like metal grafts, are extensively used. After the operation, stents are inserted within vessels to support vessels. Recently, there has been a tendency toward the expansion of their use. Made of stainless steel, tantalum or titanium-nickel, stents are fabricated into a variety of forms, including balloons and tubes. However, statistics show that restenosis occurs at a rate of 20-30%, on average, even after the implantation of stents. It is found that the failure is attributed mainly to the fact that acute and chronic thrombosis is generated or smooth muscle cells on the inner wall of blood vessels abnormally proliferate owing to injuries formed upon the stent operation.
Because metal surfaces are positively charged in general so that they strongly interact with blood, which contains negative charges, to form thrombus very easily thereon. In addition, the large critical surface tension of metal is described to be another reason for high thrombogenecity (M. F. A. Goosen et al., Biomaterials 17, 685-694, 1996).
A variety of modifications of stents for improvement in antithrombogenicity and biocompatibility are known.
In U.S. Pat. Nos. 5,824,045 yielded to E. Alt and U.S. Pat. No. 5,976,169 yielded to M. A. Imran, gold, platinum, silver or alloys thereof are vapor-deposited onto stents made of stainless steel with the aim of reducing allergic responses and improving antithrombogenicity. The resultant effects were not excellent. A. J. Armini teaches the introduction of beta emission in a stent preventive of restenosis. His U.S. Pat. No. 5,824,045 discloses a coronary stent with a radioactive, radio-opaque coating into which beta-emitting radioisotope ions are implanted. As for the coating, it is formed by vapor-depositing gold, platinum, tantalum or some combination or alloy thereof onto the structural material based on stainless steel, titanium or nickel-titanium alloy.
Because of the absence of chemically active functional groups, metal, unlike organic materials such as polymers, is virtually impossible to chemically modify. Although there are some examples of modification of the surfaces of metal materials, especially, stents, with PEG, polyvinyl alcohol, or other hydrophilic polymers (U.S. Pat. No. 5,843,172 yielded to J. Y. Yan and U.S. Pat. No. 5,897,911 yielded to J. P. Loeffler), the applications are nothing but mere coatings poor in adhesion, so that the antithrombogenicity effects thus obtained are not of a satisfactory level.
Additionally, extensive research has been directed to the coating of polymers onto stents in order to provide antithrombogenicity to the stents. For instance, there have been suggested methods of covering nylon nets (T. Yoshioka, et al., Am. J. Radiol, 15, 673-676, 1988), and coating with silicon (T. Roeren et al., Radiology 174, 1069, 1990) and polyurethane (I. K. De Scheerder et al., J. Am. Coll. Cardiol. 23, 186A, 1994). No satisfactory results were obtained in these studies, either.
Additionally, relevant studies can be found in S. Stheth et al, J. Am. Coll. Cardiol., 23, 187A, 1994, which describes the coating of polymers on medical metal substrates such as stents and catheters; R. S. Schwartz et al., J. Am. Coll. Cardiol., 19, 171A, 1992, which uses fibrin as a coating on stents; and A. M. Lincoff et al., J. Am. Coll. Cardiol., 23, 18A, 1994, in which a medicine-containing polymer is used as a coating on a medical metal substrate to achieve the sustained release of the medicine. These techniques are found to be unable to ensure antithrombogenicity in medical metal substrates.
Heparin, a well known anticoagulant is widely used in the clinic when treating with artificial kidneys or artificial cardiopulmonary machines. Besides antithrombogenicity, heparin was reported to have the function of inhibiting the proliferation of smooth muscle cells (Guyton et al., xe2x80x9cInhibition of rat arterial smooth muscle cell proliferation by heparinxe2x80x9d, Cir. Res., 46, 625-634, 1980; Cavender et al., xe2x80x9cThe effects of heparin bonded tantalum stents on thrombosis and neointimal proliferationxe2x80x9d Circulation 82, 111-541, 1990). When heparin is bonded to medical metallic substrates, especially stents, they are expected to perform their functions without restenosis by virtue of the heparin""s effects, including the prevention of thrombogenesis and the inhibition of the proliferation of smooth muscle cells on vessel walls.
Heparin is a polydispersed, negatively charged polysaccharide synthesized in the body. With a structure of a glycosaminoglycan, heparin has a large amount of sulfonic acid groups and small amounts of carboxylic acid groups, hydroxyl groups and amino groups. Naturally, heparin is synthesized with a molecular weight ranging from 7,000 to 20,000. From this high molecular weight heparin, heparin with a weight of 2,000-5,000 can be prepared. This low molecular weight heparin was reported to be superior in antithrombogenicity to the high molecular weight heparin (R. D. Rosenberg, Heparin: New biomedical and medical aspects, W. De Gruyter, Berlin, 1983). Further, when it is desired, heparin can be degraded by suitable methods such as oxidation (F. Lundberg et al., Biomaterials 19, 1727-1733, 1998).
Medical products in current use, such as catheters, blood tubes, etc., are improved in antithrombogenicity by physically coating or chemically bonding heparin onto substrates (e.g., J. M. Toomasian etc., xe2x80x9cEvaluation of Duraflo II heparin coating in prolonged extra-corporeal membrane oxygenationxe2x80x9d, ASAIO Trans., 34, 410-414, 1988; J. Sanchez etc., xe2x80x9cControl of contact activation on end-point immobilized heparinxe2x80x9d, J. Biomed. Material Res., 29, 655-651, 1995). In many relevant articles and patents, a variety of techniques for coating or bonding heparin are suggested. For instance, before the application of heparin, substrates are first coated with cationic compounds or polymers in order to link negatively charged heparin to the substrates via ionic bonds. Another example is that polymers or hydrogel in which heparin is dispersed or dissolved are coated onto substrates. However, the heparin coated in these techniques is not permanent because it is slowly released into blood or injection solutions. Also, reported are a heparin-containing polymer (U.S. Pat. No. 5,980,972 yielded to N. Ding et al.) and heparin-containing hydrogel (U.S. Pat. No. 5,954,706 yielded to R. A. Sahatjian et al.) for releasing drug in controlled patterns without causing thrombogenesis. The coated heparin of these releasing systems does not show permanent effects, as well, for the same reason as above.
Estradiol derivatives functioning as female hormones, especially 17xcex2-estradiol, are disclosed to inhibit proliferation of the smooth muscle cells in the walls of blood vessels, so that they can be used to effectively restrain restenosis (T. F. Luescher et al., xe2x80x9c17xcex2-Estradiol inhibits proliferation and migration of human vascular smooth muscle cellsxe2x80x9d, Cardiovascular Research 32, 980-985, 1996). Since then, the therapy using estradiol and its derivatives has been under study, but there have been yet reported studies in which estradiol or its derivatives are grafted onto metallic materials in order to permanently express the functions thereof.
Leading to the present invention, intensive and thorough research on the adaptation of metallic materials to biological circumstances, conducted by the present inventors aiming to overcome problems encountered in prior arts, resulted in the finding that biologically active materials, such as heparin and estradiol derivatives, can be grafted onto metallic materials by use of sulfur compounds absorbed in gold or silver layer stably deposited onto the metallic materials, thereby surprisingly improving the metallic materials in antithrombogenicity and biocompatibility. On the surface of a metallic material of the present invention, a gold or silver thin layer is stably coated, to which sulfur compounds are strongly adsorbed, forming charge transfer complexes, and chemically bonded with biologically active materials, such as heparin or estradiol derivatives.
Therefore, it is an object of the present invention to provide a medical metallic material whose surface is modified by coating a gold or silver thin layer onto a base metal by use of a electroplating method, a vacuum vapor deposition method or an ion sputtering method, firmly adsorbing a sulfur compound onto the gold or silver thin layer, and securely grafting a biologically active material such as heparin or an estradiol derivative to the adsorbed sulfur compound, thereby greatly improving the base metal in antithrombogenicity and biocompatibility.
It is another object of the present invention to provide a method for preparing such a medical, metallic material.
It is a further object of the present invention to provide the use of such a medical metallic material in various medical applications, including devices for circulatory systems.